Monoclonal antibodies (MAbs) have demonstrated clinical effectiveness in a variety of malignancies. Monoclonal antibodies are now being commonly used as therapeutic agents for the treatment and/or prevention of cancers, autoimmune diseases, thrombosis, inflammation, and infection. However, there are some instances of low antibody activity contributing to insufficient therapeutic effects on cancers, autoimmune diseases, inflammation, and infection. Such insufficient drug action may lead to increased dosages and cost required for treatment. Under these circumstances, enhancement of the therapeutic activity of the monoclonal antibodies is an important objective.
Therapeutic monoclonal antibodies are preferably capable of antibody-dependent cellular cytotoxicity (ADCC), particularly when used in the treatment of cancers or other cellular diseases. That is, therapeutic MAbs preferably exert cytotoxic effects against their target cells, such as target cancer cells or lymphocytes. Such antibodies bind to antigens on the surface of target cells, via their Fc domain, to Fc receptors on the surface of effector cells such as NK cells and macrophages, thereby exerting damage on target cells. This mechanism is antibody-dependent cellular cytotoxicity (ADCC). Alternatively, antibodies damage cells by activating complement via the Fc domain. This is called complement-dependent cytotoxicity (CDC). Such antibody activities exerted via Fc domains are called effector activities.
There have been various attempts to enhance the effector function of antibodies with the aim of enhancing their therapeutic activity. Several types of effector cells, such as monocytes, neutrophils, and natural killer (NK) cells, have surface receptors that bind the Fc portion of immunoglobulins. Effector cells for inducing ADCC against a target cell include human leukocytes, macrophages, monocytes, activated neutrophils, and possibly activated natural killer (NK) cells and eosinophils. Preferred effector cells express FcγRI and include, for example, monocytes and activated neutrophils. Expression of FcγRI has been found to be up-regulated by interferon gamma (IFN-γ). This enhanced expression increases the cytotoxic activity of monocytes and neutrophils against target cells.
An Fc receptor is a protein found on the surface of certain cells—including natural killer cells, macrophages, neutrophils, and mast cells—that contribute to the protective functions of the immune system. Fc receptors bind to antibodies that are attached to infected cells, invading pathogens, or cancer cells. Their activity stimulates phagocytic or cytotoxic cells to destroy microbes, infected cells, or cancer cells by antibody-mediated phagocytosis or ADCC. Some viruses such as flaviviruses use Fc receptors to help them infect cells, by a mechanism known as antibody-dependent enhancement of infection. Fc receptors are involved in ADCC process. For example, during ADCC FcγRIII receptors on the surface of natural killer (NK) cells stimulate the NK cells to release cytotoxic molecules from their granules to kill antibody-covered target cells.
There are several different types of Fc receptors, which are classified based on the type of antibody that they recognize. One group of IgG Fc receptors, FcγRs belong to the immunoglobulin superfamily and are the most important Fc receptors for inducing phagocytosis of opsonized (coated) microbes. They are expressed on leukocytes and are composed of 3 distinct classes: FcγRI, FcγRII (FcγRIIa and FcγRIIb), FcγRIII (FcγRIIIa and FcγRIIIb). The receptors are also distinguished by their affinity for IgG. FcγRI exhibits high affinity for IgG, whereas FcγRII and FcγRIII show a weaker affinity. FcγRIIa and FcγRIIIa are activating FcγRs which are expressed on monocytes/macrophages and monocytes/macrophages/NK cells, respectively, and can trigger cytotoxicity of human targets.
Two functional FcγR gene polymorphisms, FcγR3a-V158F and FcγR2a-H131R, have been identified that affect the binding of IgG, changing ADCC function and affecting clinical tumor response. FcγR2a-H131R polymorphism is located at the extracellular ligand-binding domain. It either has a histidine (H) or arginine (R) allele at amino acid position 131. The FcγR2a-131H/H genotype has a higher affinity to human IgG2 in an in vitro assay. FcγR3a-V158F polymorphism encodes either a valine (V) or phenylalanine (F) at amino acid position 158. In vitro studies have shown that FcγR3a V allele has a higher binding affinity to human IgG1 than the F allele, indicating immune effector cells bearing FcγR3a V allele mediate ADCC more effectively (Zhang et al. J. of Clinical Oncology, 25: 3712-3718, 2007).
A further need exists to improve the therapeutic effectiveness of monoclonal antibodies. There is a need to enhance effector function of antibodies, for example enhancing the ADCC and/or CDC function of antibodies.
Throughout this description, including the foregoing description of related art, any and all publicly available documents described herein, including any and all U.S. patents, are specifically incorporated by reference herein in their entirety. The foregoing description of related art is not intended in any way as an admission that any of the documents described therein, including pending United States patent applications, are prior art to embodiments of the present disclosure. Moreover, the description herein of any disadvantages associated with the described products, methods, and/or apparatus, is not intended to limit the disclosed embodiments. Indeed, embodiments of the present disclosure may include certain features of the described products, methods, and/or apparatus without suffering from their described disadvantages.